dbSNP rs10484922: ESR1:c.452+2818C>T (chr6-151811182-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000125.4(ESR1):c.452+2818C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 152,100 control chromosomes in the GnomAD database, including 600 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.081 ( 600 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ESR1
NM_000125.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.110

Publications

17 publications found

Variant links:

Genes affected

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ESR1 Gene-Disease associations (from GenCC):

estrogen resistance syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ESR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.452+2818C>T		intron_variant	Intron 1 of 7	ENST00000206249.8	NP_000116.2	P03372-1G4XH65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 link	c.452+2818C>T		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.0807

AC:

12270

AN:

151982

Hom.:

600

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0786

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.0363

Gnomad ASJ

AF:

0.0657

Gnomad EAS

AF:

0.00635

Gnomad SAS

AF:

0.0390

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0923

Gnomad OTH

AF:

0.0669

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.0807

AC:

12278

AN:

152100

Hom.:

600

Cov.:

AF XY:

0.0808

AC XY:

6005

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0786

AC:

3260

AN:

41500

American (AMR)

AF:

0.0363

AC:

555

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0657

AC:

228

AN:

3470

East Asian (EAS)

AF:

0.00636

AC:

AN:

5188

South Asian (SAS)

AF:

0.0392

AC:

189

AN:

4820

European-Finnish (FIN)

AF:

0.140

AC:

1472

AN:

10544

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0923

AC:

6273

AN:

67968

Other (OTH)

AF:

0.0662

AC:

140

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

564

1128

1691

2255

2819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0838

Hom.:

199

Bravo

AF:

0.0721

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.8

(source)

DANN

Benign

0.71

PhyloP100

-0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over